EP3733650A1 - Method for preparing elagolix intermediate and composition thereof - Google Patents
Method for preparing elagolix intermediate and composition thereof Download PDFInfo
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- EP3733650A1 EP3733650A1 EP18895688.2A EP18895688A EP3733650A1 EP 3733650 A1 EP3733650 A1 EP 3733650A1 EP 18895688 A EP18895688 A EP 18895688A EP 3733650 A1 EP3733650 A1 EP 3733650A1
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- 238000000034 method Methods 0.000 title claims abstract description 27
- HEAUOKZIVMZVQL-VWLOTQADSA-N Elagolix Chemical compound COC1=CC=CC(C=2C(N(C[C@H](NCCCC(O)=O)C=3C=CC=CC=3)C(=O)N(CC=3C(=CC=CC=3F)C(F)(F)F)C=2C)=O)=C1F HEAUOKZIVMZVQL-VWLOTQADSA-N 0.000 title claims abstract description 12
- 229950004823 elagolix Drugs 0.000 title claims abstract description 12
- 239000000203 mixture Substances 0.000 title claims description 47
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 49
- 150000001875 compounds Chemical class 0.000 claims description 45
- 238000006243 chemical reaction Methods 0.000 claims description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 238000005915 ammonolysis reaction Methods 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 238000010606 normalization Methods 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 239000011734 sodium Substances 0.000 abstract description 2
- 229910052708 sodium Inorganic materials 0.000 abstract description 2
- 238000003912 environmental pollution Methods 0.000 abstract 1
- 239000012044 organic layer Substances 0.000 description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 30
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 28
- 239000008213 purified water Substances 0.000 description 26
- 230000000717 retained effect Effects 0.000 description 21
- 230000015572 biosynthetic process Effects 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- IJRKKZXPXBTHER-UHFFFAOYSA-N 1-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-methylpyrimidine-2,4-dione Chemical compound CC1=CC(=O)NC(=O)N1CC1=C(F)C=CC=C1C(F)(F)F IJRKKZXPXBTHER-UHFFFAOYSA-N 0.000 description 15
- RJNJWHFSKNJCTB-UHFFFAOYSA-N benzylurea Chemical compound NC(=O)NCC1=CC=CC=C1 RJNJWHFSKNJCTB-UHFFFAOYSA-N 0.000 description 14
- 238000010992 reflux Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 11
- 239000012535 impurity Substances 0.000 description 10
- JKUYRAMKJLMYLO-UHFFFAOYSA-N tert-butyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OC(C)(C)C JKUYRAMKJLMYLO-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 201000009273 Endometriosis Diseases 0.000 description 2
- 102000008238 LHRH Receptors Human genes 0.000 description 2
- 108010021290 LHRH Receptors Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- WOFAGNLBCJWEOE-UHFFFAOYSA-N Benzyl acetoacetate Chemical compound CC(=O)CC(=O)OCC1=CC=CC=C1 WOFAGNLBCJWEOE-UHFFFAOYSA-N 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- NLKRQVSNIXWLBR-UHFFFAOYSA-N NC(NCc1c(C(F)(F)F)cccc1F)=O Chemical compound NC(NCc1c(C(F)(F)F)cccc1F)=O NLKRQVSNIXWLBR-UHFFFAOYSA-N 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- YPJUNDFVDDCYIH-UHFFFAOYSA-N perfluorobutyric acid Chemical compound OC(=O)C(F)(F)C(F)(F)C(F)(F)F YPJUNDFVDDCYIH-UHFFFAOYSA-N 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- AXLMPTNTPOWPLT-UHFFFAOYSA-N prop-2-enyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OCC=C AXLMPTNTPOWPLT-UHFFFAOYSA-N 0.000 description 1
- GVIIRWAJDFKJMJ-UHFFFAOYSA-N propan-2-yl 3-oxobutanoate Chemical compound CC(C)OC(=O)CC(C)=O GVIIRWAJDFKJMJ-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention belongs to the field of pharmaceutical chemistry, in particular relates to a method for preparing an intermediate of elagolix and a composition comprising the intermediate.
- Endometriosis is a common and frequently-occurring gynecological disease, which is a common benign infiltrative disease common to women in childbearing age and is one of the gynecological intractable diseases.
- the prevalence rate of middle-aged women is about 15%. The disease usually begins mostly between 30-49 years old. Women in childbearing age suffering from this disease account for 70%-80% of infertility patients, which seriously affects women's physical and mental health, work and fertility.
- Elagolix is an orally active non-peptide gonadotropin-releasing hormone receptor (GnRH) antagonist developed by AbbVie and Neurocrine Biosciences Inc. (NBIX) for the treatment of endometriosis.
- GnRH gonadotropin-releasing hormone receptor
- NBIX Neurocrine Biosciences Inc.
- the route uses toxic and explosive diketene, which has high safety risks and is not suitable for industrial production.
- the yield of this synthetic route is only 62%, and we repeated this route with a yield of only 57%.
- the yield of this synthetic route is relatively low, resulting in a large amount of material waste and an increase in cost.
- the post-treatment needs to be stirred overnight and the process time is long, which is not suitable for industrial production.
- a large amount of impurity exists along with the compound of Formula IV, which make the purification difficult.
- the present invention is accomplished, in order to overcome the defects of using toxic reagents, low yield, troublesome post-treatment and the like during the process for preparing the compound of Formula IV of the intermediate of elagolix in the prior art.
- the present invention mainly relates to a method for preparing an intermediate of sodium elagolix, which is represented by Formula IV.
- the first aspect of the present invention is to provide a method for preparing a compound of Formula IV comprising steps of: carrying out ammonolysis reaction of a compound of Formula I and a compound of Formula II in a mixed solvent of organic solvent and water, and then carrying out cyclization reaction catalyzed by acid to obtain the compound of Formula IV.
- R is selected from a group consisting of linear or branched C 1 -C 4 substituents or benzyl.
- the linear or branched C 1 -C 4 substituent is alkyl or alkenyl.
- the alkyl is preferably methyl, ethyl, isopropyl or tert-butyl.
- the alkenyl group is preferably allyl.
- the organic solvent is an aprotic organic solvent.
- the aprotic organic solvent is one or more selected from a group consisting of toluene, chlorobenzene, xylene, N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). More preferably, the organic solvent is toluene.
- the method for preparing the compound of Formula IV comprises steps of:
- the volume ratio of the organic solvent to water is 1: 0.001-2; and more preferably 1: 0.1-1.0.
- the mass ratio of the compound of Formula I to the compound of Formula II is 1: 0.66-4, more preferably 1: 1.5-2.0.
- the ratio of the mass of the compound of Formula II to the volume of the mixed solvent is 1: 8 to 1: 20 (g/ml).
- the reaction temperature of the ammonolysis reaction is 80 °C to 150 °C, preferably 100 °C to 120 °C.
- the reaction temperature of the cyclization reaction catalyzed by acid is 40 °C to 150°C, preferably 60 °C to 120 °C, and the time for reaction is 0.5h to 6h, preferably 1h to 3h.
- the acid is selected from a group consisting of p-toluenesulfonic acid, methanesulfonic acid, and sodium dihydrogen phosphate; more preferably the acid is p-toluenesulfonic acid.
- the mass ratio of the compound of Formula II to the acid is 1: 0.5 ⁇ 1.5.
- the inventors of the present invention found that the impurities of Formula III-imp produced in the reaction can be re-converted into the raw materials of Formula I and Formula II (instead of almost all of them being converted into Formula IV-imp) in the presence of water when the mixed solvent of organic solvent and water is used as the reaction solvent in the synthesis of the compound of Formula III, so that the raw materials can be further fully converted into Formulas III and IV.
- the production of the impurities of Formula IV-imp is reduced, the utilization rate of the raw materials is improved, and the yield is obviously further improved.
- the reaction solvent, water and the organic solvent is easy to be recovered, thus reducing the treatment cost of the wastes.
- the reaction condition is mild, and the method has the advantages of simple post-treatment, high yield, and suitability for industrialization and the like.
- the reaction mechanism is shown as follows:
- the second aspect of the present invention is to provide a composition
- a composition comprising a compound of Formula IV with a content of not less than 99.5% of and a compound of Formula IV-imp with a content of not more than 0.5%, wherein the contents of both are determined by an HPLC area normalization method.
- the composition can be used for preparing high-purity elagolix.
- the compound of Formula IV is prepared by the aforementioned method.
- Embodiments of the present invention include, but are not limited to, the following examples, which should not be considered as limiting the protection scope of the present invention.
- Example 1 Comparison of results obtained from different batches of examples Batch Content of the compound of Formula IV (%) Content of the compound of Formula IV-imp (%) Yield (%) Example 1 99.77% 0.02% 82% Example 2 99.57% 0.01% 81% Example 3 99.68% 0.03% 81% Example 4 99.64% 0.21% 78% Example 5 99.58% 0.19% 77% Example 6 99.61% 0.08% 76% Example 7 99.57% 0.17% 77% Example 8 99.74% 0.03% 81% Example 9 99.54% 0.24% 77% Example 10 99.63% 0.27% 78% Example 11 99.57% 0.17% 77% Example 12 99.64% 0.28% 76% Example 13 99.58% 0.33% 76% Comparative Example 1 93.46% 6.10% 57%
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
- The present invention belongs to the field of pharmaceutical chemistry, in particular relates to a method for preparing an intermediate of elagolix and a composition comprising the intermediate.
- Endometriosis is a common and frequently-occurring gynecological disease, which is a common benign infiltrative disease common to women in childbearing age and is one of the gynecological intractable diseases. The prevalence rate of middle-aged women is about 15%. The disease usually begins mostly between 30-49 years old. Women in childbearing age suffering from this disease account for 70%-80% of infertility patients, which seriously affects women's physical and mental health, work and fertility. Elagolix is an orally active non-peptide gonadotropin-releasing hormone receptor (GnRH) antagonist developed by AbbVie and Neurocrine Biosciences Inc. (NBIX) for the treatment of endometriosis. At present, the drug has submitted an application to FDA. Its structural formula is shown by Formula I:
- There are only a few reports about the compound of Formula IV as a key intermediate for preparing the elagolix.
-
- The route uses toxic and explosive diketene, which has high safety risks and is not suitable for industrial production.
- Another synthetic route reported in
WO 2009062087 A1 is as follows. - The yield of this synthetic route is only 62%, and we repeated this route with a yield of only 57%. The yield of this synthetic route is relatively low, resulting in a large amount of material waste and an increase in cost. Moreover, the post-treatment needs to be stirred overnight and the process time is long, which is not suitable for industrial production. And a large amount of impurity exists along with the compound of Formula IV, which make the purification difficult.
- Therefore, it is of great significance to develop a new method for preparing intermediate of elagolix.
- The present invention is accomplished, in order to overcome the defects of using toxic reagents, low yield, troublesome post-treatment and the like during the process for preparing the compound of Formula IV of the intermediate of elagolix in the prior art. The present invention mainly relates to a method for preparing an intermediate of sodium elagolix, which is represented by Formula IV.
- The first aspect of the present invention is to provide a method for preparing a compound of Formula IV comprising steps of: carrying out ammonolysis reaction of a compound of Formula I and a compound of Formula II in a mixed solvent of organic solvent and water, and then carrying out cyclization reaction catalyzed by acid to obtain the compound of Formula IV.
- The linear or branched C1-C4 substituent is alkyl or alkenyl. The alkyl is preferably methyl, ethyl, isopropyl or tert-butyl. The alkenyl group is preferably allyl.
- The organic solvent is an aprotic organic solvent. Preferably, the aprotic organic solvent is one or more selected from a group consisting of toluene, chlorobenzene, xylene, N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO). More preferably, the organic solvent is toluene.
- Specifically, the method for preparing the compound of Formula IV comprises steps of:
- (1) mixing a compound of Formula I, a compound of Formula II, organic solvent and water, performing reflux reaction, stratifying the reaction system after the reaction, and keeping an organic layer;
- (2) adding acid into the organic layer to continue the reaction, and performing separation and purification after the reaction to obtain the compound of Formula IV.
- Preferably, the volume ratio of the organic solvent to water is 1: 0.001-2; and more preferably 1: 0.1-1.0.
- Preferably, the mass ratio of the compound of Formula I to the compound of Formula II is 1: 0.66-4, more preferably 1: 1.5-2.0.
- Preferably, the ratio of the mass of the compound of Formula II to the volume of the mixed solvent is 1: 8 to 1: 20 (g/ml).
- Preferably, the reaction temperature of the ammonolysis reaction is 80 °C to 150 °C, preferably 100 °C to 120 °C.
- Preferably, the reaction temperature of the cyclization reaction catalyzed by acid is 40 °C to 150°C, preferably 60 °C to 120 °C, and the time for reaction is 0.5h to 6h, preferably 1h to 3h.
- Preferably, the acid is selected from a group consisting of p-toluenesulfonic acid, methanesulfonic acid, and sodium dihydrogen phosphate; more preferably the acid is p-toluenesulfonic acid.
- Preferably, the mass ratio of the compound of Formula II to the acid is 1: 0.5 ∼ 1.5.
- Studies have found that during the process for synthesizing the compound of Formula III according to the method in
WO 2009062087 A1 , when toluene is used as a reaction solvent then acidification reaction is carried out, a large amount of impurities of Formula IV-imp are generated, and the polarity of the impurities is relatively similar to that of the compound of Formula IV. Several times of crystallization are needed to remove the impurities, but these impurities cannot be completely removed, which results in that the post-treatment is troublesome and available materials are wasted. - After repeated experiments, the inventors of the present invention found that the impurities of Formula III-imp produced in the reaction can be re-converted into the raw materials of Formula I and Formula II (instead of almost all of them being converted into Formula IV-imp) in the presence of water when the mixed solvent of organic solvent and water is used as the reaction solvent in the synthesis of the compound of Formula III, so that the raw materials can be further fully converted into Formulas III and IV. Thus the production of the impurities of Formula IV-imp is reduced, the utilization rate of the raw materials is improved, and the yield is obviously further improved. The reaction solvent, water and the organic solvent, is easy to be recovered, thus reducing the treatment cost of the wastes. The reaction condition is mild, and the method has the advantages of simple post-treatment, high yield, and suitability for industrialization and the like. The reaction mechanism is shown as follows:
- The second aspect of the present invention is to provide a composition comprising a compound of Formula IV with a content of not less than 99.5% of and a compound of Formula IV-imp with a content of not more than 0.5%, wherein the contents of both are determined by an HPLC area normalization method. The composition can be used for preparing high-purity elagolix. Preferably, the compound of Formula IV is prepared by the aforementioned method.
-
- 1. Compared with the prior art, the present invention avoids further generation of the impurity compound of Formula IV-imp in case that the compound of Formula III-imp is generated, thereby reducing the presence of the impurity compound of Formula IV-imp in the compound of the Formula IV. The present invention not only improves the yield, but also solves the problems that the impurity is difficult to be removed and the post-treatment is troublesome. Further, in the present invention, the operation is simple and convenient, and the manufacturing cost is reduced.
- 2. In the present invention, the reaction solvent, water and the organic solvent, is easy to be recovered, the reaction conditions are mild, and the method has the advantages of simple post-treatment, suitability for industrialization and the like.
- Hereinafter, embodiments of the present invention will be described in detail with reference to examples. Embodiments of the present invention include, but are not limited to, the following examples, which should not be considered as limiting the protection scope of the present invention.
- The synthesis of the raw material, a compound of Formula II can refer to the prior art
CN100424078C , the entire content of which is incorporated herein by reference. - HPLC analysis conditions for measuring the content of the compound of Formula IV and the compound of Formula IV-imp are shown as follows.
Column: Waters Xbridge-Phenyl 4.6∗150 mm 3.5µm
Eluent A: 1.0 ml of perfluorobutyric acid in 1L of water (%V/V)
Eluent B: MEOH:ACN=1:1(%V/V)
Gradient:Time (min) Eluent A Eluent B 0.00 60 40 17 30 70 20 30 70 20.1 60 40 30 60 40
Running time: 30min
Sample volume: 10 µL
Detector: 265nm
Column temperature: 30°C -
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (100g), tert-butyl acetoacetate (194.2g), toluene (1000ml) and purified water (100ml) were added to a 2L flask and stirred for reflux reaction for 6h. The reaction system was stratified and the upper organic layer was retained. P-toluenesulfonic acid monohydrate (104g) was added to the obtained organic layer, and thus obtained mixture was stirred and reacted at 60°C for 2h. Then, the mixture was cooled to room temperature and was stirred. Purified water (300ml) was added thereto under stirring. The mixture was stratified, the upper organic layer was retained and concentrated, and crystallized in isopropanol to obtain 104.9g of the compound of Formula IV with a yield of 82%. The results were shown in Table 1. 1H NMR (400 MHz, CDCl3) δ 2.15(s, 3H), 5.37 (s, 2H), 5.60 (s, 2H), 7.23∼7.56 (m, 3H), 9.02(s, 1H). MS(ESI) m/z 303.0([M+H]+).
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (30g), tert-butyl acetoacetate (58.3g), toluene (300ml) and purified water (50ml) were added to a 1L flask and stirred for reflux reaction for 6h. The reaction system was stratified and the upper organic layer was retained. P-toluenesulfonic acid monohydrate (31.2g) was added to the obtained organic layer, and thus obtained mixture was stirred and reacted at 60 °C for 2h. Then, the mixture was cooled to room temperature and was stirred. Purified water (90ml) was added thereto under stirring. The mixture was stratified, the upper organic layer was retained and concentrated, and thus obtained product was crystallized in isopropanol to obtain 31.1g of the compound of Formula IV with a yield of 81%. MS(ESI) m/z 303.0([M+H]+). The results were shown in table 1.
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (50g), tert-butyl acetoacetate (94.1g), toluene (500ml) and purified water (500ml) were added to a 1L flask and stirred for reflux reaction for 6h. The reaction system was stratified and the upper organic layer was retained. P-toluenesulfonic acid monohydrate (52g) was added to the obtained organic layer, and thus obtained mixture was stirred and reacted at 60 °C for 2h. Then, the mixture was cooled to room temperature and was stirred. Purified water (150ml) was added thereto under stirring. The mixture was stratified, the upper organic layer was retained and concentrated, and thus obtained product was crystallized in isopropanol to obtain 60.9g of the compound of Formula IV with a yield of 81%. MS(ESI) m/z 303.0([M+H]+). The results were shown in table 1.
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (50g), tert-butyl acetoacetate (94.1g), chlorobenzene (500ml) and purified water (100ml) were added to a 1L flask and stirred for reflux reaction for 6h. The reaction system was stratified and the upper organic layer was retained. P-toluenesulfonic acid monohydrate (52g) was added to the obtained organic layer, and thus obtained mixture was stirred and reacted at 60°C for 2h. Then, the mixture was cooled to room temperature and was stirred. Purified water (150ml) was added thereto under stirring. The mixture was stratified, the upper organic layer was retained and concentrated, and thus obtained product was crystallized in isopropanol to obtain 49.9g of the compound of Formula IV with a yield of 78%. MS(ESI) m/z 303.0([M+H]+). The results were shown in table 1.
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (25g), tert-butyl acetoacetate (47g), xylene (250ml) and purified water (200ml) were added to a 1L flask and stirred for reflux reaction for 6h. The reaction system was stratified and the upper organic layer was retained. P-toluenesulfonic acid monohydrate (27g) was added to the obtained organic layer, and thus obtained mixture was stirred and reacted at 60 °C for 2h. Then, the mixture was cooled to room temperature and was stirred. Purified water (75ml) was added thereto under stirring. The mixture was stratified, the organic layer was retained and concentrated, and thus obtained product was crystallized in isopropanol to obtain 24.6g of the compound of Formula IV with a yield of 77%. MS(ESI) m/z 303.0([M+H]+). The results were shown in table 1.
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (30g), tert-butyl acetoacetate (58.3g), N,N-dimethylformamiade (300ml) and purified water (300ml) were added to a 1L flask and stirred at 120 °C to react for 4h. The reaction system was cooled and concentrated. Toluene (300ml), p-toluenesulfonic acid monohydrate (31g) were added to the obtained concentrate. The mixture was stirred and reacted at 60 °C for 2h. Then, the mixture was cooled to room temperature and was stirred. Purified water (75ml) was added thereto under stirring. The mixture was stratified, the upper organic layer was retained and concentrated, and thus obtained product was crystallized in isopropanol to obtain 29.1g of the compound of Formula IV with a yield of 76%. MS(ESI) m/z 303.0([M+H]+). The results were shown in table 1.
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (30g), tert-butyl acetoacetate (58.3g), dimethyl sulfoxide (300ml) and purified water (150ml) were added to a 1L flask and stirred at 120 °C to react for 4h. The reaction system was cooled, and p-toluenesulfonic acid monohydrate (31g) was added thereto and stirred. The mixture was reacted at 60°C for 2h. Then, the mixture was cooled to room temperature and was stirred. Purified water (150ml) was added thereto, and the obtained mixture was extracted with ethyl acetate. The organic layer was washed with saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and thus obtained product was crystallized in isopropanol to obtain 29.6g of the compound of Formula IV with a yield of 77%. MS(ESI) m/z 303.0([M+H]+). The results were shown in table 1.
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (25g), tert-butyl acetoacetate (47g), toluene (250ml) and purified water (150ml) were added to a 1L flask and stirred for reflux reaction for 6h. The reaction system was stratified and the upper organic layer was retained. P-toluenesulfonic acid monohydrate (27g) was added to the obtained organic layer, and thus obtained mixture was stirred and reacted at 60 °C for 2h. Then, the mixture was cooled to room temperature and was stirred. Purified water (75ml) was added thereto under stirring. The mixture was stratified, the upper organic layer was retained and concentrated, and thus obtained product was recrystallized in isopropanol to obtain 31.1g of the compound of Formula IV with a yield of 81%. MS(ESI) m/z 303.0([M+H]+). The results were shown in table 1.
-
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (50g), ethyl acetoacetate (63.9g), toluene (500ml) and purified water (200ml) were added to a 1L flask and stirred for reflux reaction for 6h. The reaction system was stratified and the upper organic layer was retained. P-toluenesulfonic acid monohydrate (52g) was added to the obtained organic layer, and thus obtained mixture was stirred and reacted at 60 °C for 2h. Then, the mixture was cooled to room temperature and was stirred. Purified water (150ml) was added thereto under stirring. The mixture was stratified, the upper organic layer was retained and concentrated, and thus obtained product was crystallized in isopropanol to obtain 48.5g of the compound of Formula IV with a yield of 77%. MS(ESI) m/z 303.0([M+H]+). The results were shown in table 1.
-
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (50g), methyl acetoacetate (71.3g), toluene (500ml) and purified water (150ml) were added to a 1L flask and stirred for reflux reaction for 6h. The reaction system was stratified and the upper organic layer was retained. P-toluenesulfonic acid monohydrate (52g) was added to the obtained organic layer, and thus obtained mixture was stirred and reacted at 60 °C for 2h. Then, the mixture was cooled to room temperature and was stirred. Purified water (150ml) was added thereto under stirring. The mixture was stratified, the upper organic layer was retained and concentrated, and thus obtained product was crystallized in isopropanol to obtain 49.0g of the compound of Formula IV with a yield of 78%. MS(ESI) m/z 303.0([M+H]+). The results were shown in table 1.
-
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (50g), isopropyl acetoacetate (88.5g), toluene (500ml) and purified water (4.5g) were added to a 1L flask and stirred for reflux reaction for 6h. The reaction system was stratified and the upper organic layer was retained. P-toluenesulfonic acid monohydrate (52g) was added to the obtained organic layer, and thus obtained mixture was stirred and reacted at 60 °C for 2h. Then, the mixture was cooled to room temperature and was stirred. Purified water (150ml) was added thereto under stirring. The mixture was stratified, the upper organic layer was retained and concentrated, and thus obtained product was crystallized in isopropanol to obtain 49.2g of the compound of Formula IV with a yield of 77%. MS(ESI) m/z 303.0([M+H]+). The results were shown in table 1.
-
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (30g), allyl acetoacetate (52.4g), toluene (300ml) and purified water (150ml) were added to a 1L flask and stirred at 120 °C to react for 4h. The reaction system was cooled, and p-toluenesulfonic acid monohydrate (31g) was added thereto and stirred. The mixture was reacted at 60 °C for 2h. Then, the mixture was cooled to room temperature and was stirred. Purified water (150ml) was added thereto, and the obtained mixture was extracted with ethyl acetate. The organic layer was washed with saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated, and thus obtained product was crystallized in isopropanol to obtain 29.1g of the compound of Formula IV with a yield of 76%. MS(ESI) m/z 303.0([M+H]+). The results were shown in table 1.
-
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (50g), benzyl acetoacetate (118g), toluene (500ml) and purified water (4.5g) were added to a 1L flask and stirred for reflux reaction for 6h. The reaction system was stratified and the upper organic layer was retained. P-toluenesulfonic acid monohydrate (52g) was added to the obtained organic layer, and thus obtained mixture was stirred and reacted at 60 °C for 2h. Then, the mixture was cooled to room temperature and was stirred. Purified water (150ml) was added thereto under stirring. The mixture was stratified, the upper organic layer was retained and concentrated, and thus obtained product was crystallized in isopropanol to obtain 48.5g of the product with a yield of 76%. MS(ESI) m/z 303.0([M+H]+). The results were shown in table 1.
- 1H NMR data of the compound of Formula IV prepared in the Examples 2 to 13 were the same as those of Example 1.
- Compound of Formula II 1-[2-fluoro-6-(trifluoromethyl)]benzyl urea (2.568g) and toluene (125ml) were added to a 1L flask and stirred for reflux, and then tert-butyl acetoacetate (5.0g) was added thereto for reflux reaction for 4h. P-toluenesulfonic acid monohydrate (2.82g) was added to the reflux system to continue the reaction for 1h. The obtained mixture was distilled to completely remove toluene, and then 30ml of isopropanol was added thereto and stirred overnight. Thus obtained mixture was filtered, and the filter cake was washed with isopropanol to obtain the compound of Formula IV 1.81g with a yield of 57%. MS(ESI) m/z 303.0([M+H]+). The results were shown in table 1.
Table 1: Comparison of results obtained from different batches of examples Batch Content of the compound of Formula IV (%) Content of the compound of Formula IV-imp (%) Yield (%) Example 1 99.77% 0.02% 82% Example 2 99.57% 0.01% 81% Example 3 99.68% 0.03% 81% Example 4 99.64% 0.21% 78% Example 5 99.58% 0.19% 77% Example 6 99.61% 0.08% 76% Example 7 99.57% 0.17% 77% Example 8 99.74% 0.03% 81% Example 9 99.54% 0.24% 77% Example 10 99.63% 0.27% 78% Example 11 99.57% 0.17% 77% Example 12 99.64% 0.28% 76% Example 13 99.58% 0.33% 76% Comparative Example 1 93.46% 6.10% 57% - The method for preparing the intermediate of elagolix according to the present invention is described in connection with examples, and those skilled in the art can obviously realize the present invention by modifying or appropriately changing and combining with the method for preparing the intermediate of elagolix described herein without departing from the content, spirit and scope of the invention. In particular, it should be understood that all similar substitutions and changes will be obvious to those skilled in the art, and they are all considered to be included in the spirit, scope and content of the present invention.
Claims (13)
- A method for preparing a compound of Formula IV, an intermediate of elagolix, comprising steps of: carrying out ammonolysis reaction of a compound of Formula I and a compound of Formula II in mixed solvent of organic solvent and water, and then carrying out cyclization reaction catalyzed by acid to obtain the compound of Formula IV;
- The method according to claim 1, wherein the linear or branched C1-C4 substituents is alkyl or alkenyl; the alkyl is preferably methyl, ethyl, isopropyl or tert-butyl; and the alkenyl is preferably allyl.
- The method according to claim 1 or 2, wherein the organic solvent is an aprotic organic solvent; preferably, the organic solvent is one or more selected from a group consisting of toluene, chlorobenzene, xylene, N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO).
- The method according to any one of claims 1 to 3, wherein the organic solvent is toluene.
- The method according to any one of claims 1 to 4, wherein the volume ratio of the organic solvent to water is 1: 0.001-2; and more preferably 1: 0.1-1.0.
- The method according to any one of claims 1 to 5, wherein the mass ratio of the compound of Formula I to the compound of Formula II is 1: 0.66-4, more preferably 1: 1.5-2.0.
- The method according to any one of claims 1 to 6, wherein the ratio of the mass of the compound of Formula II to the volume of the mixed solvent is 1: 8 to 1: 20 with a unit of g/ml.
- The method according to any one of claims 1 to 7, wherein the reaction temperature of the ammonolysis reaction is 80 °C to 150 °C, preferably 100 °C to 120 °C.
- The method according to any one of claims 1 to 8, wherein the reaction temperature of the cyclization reaction catalyzed by the acid to prepare the compound of Formula IV is 40 °C to 150°C, preferably 60 °C to 120 °C.
- The method according to any one of claims 1 to 9, wherein the acid is selected from a group consisting of p-toluenesulfonic acid, methanesulfonic acid, and disodium hydrogen phosphate; preferably the acid is p-toluenesulfonic acid.
- The method according to any one of claims 1 to 10, wherein the mass ratio of the compound of Formula II to the acid is 1: 0.5-1.5.
- The composition according to claim 12, wherein the mass percentages are determined by an HPLC area normalization method.
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CN110501446B (en) * | 2019-08-28 | 2021-12-17 | 江苏海岸药业有限公司 | Analysis method of oxa-goril sodium raw material and synthetic intermediate thereof |
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